Elucidating Determinants of Gestational Beta-Cell Adaptation and Failure The candidate is an M.D. trained in clinical endocrinology who will undertake a five-year mentored research and career development program in the genetics, physiology, and endocrinology of glucose metabolism in pregnancy at Massachusetts General Hospital (MGH). The candidate will complete the proposed program under the mentorship of prominent researchers with complementary areas of expertise: 1) Dr. Jose C. Florez, Chief of the MGH Diabetes Unit and world-recognized leader in translational investigation of type 2 diabetes genetics and 2) Dr. Ravi Thadhani, Chief of the MGH Nephrology Division and expert in translational investigation of medical disorders in pregnancy. The candidate will undertake coursework, receive mentorship, and gain practical experience in physiologic investigation, longitudinal and genetic data analysis, advanced techniques to profile human plasma, and safe, ethical conduct of research in the obstetric population. This program will uniquely equip the candidate with the skills necessary to become an independent physician-scientist investigating endocrine and metabolic disease in pregnancy. Indeed, during pregnancy, there are profound changes in glucose metabolism. By late gestation, maternal pancreatic beta cells must dramatically increase insulin secretion in the face of marked pregnancy-induced insulin resistance. In 5-10% of pregnant women, this beta-cell adaptation fails, resulting in gestational diabetes mellitus (GDM). GDM is associated with costly adverse perinatal outcomes and a high risk of future maternal type 2 diabetes. It is unclear to what extent GDM results from maternal beta-cell defects that preceded pregnancy or from an imbalance of circulating hormones that stimulate the beta cell during gestation. The scientific goal of the proposed research is to assess the contribution of maternal genetics and circulating gestational hormones to beta-cell adaptation and failure in pregnancy. In Aim 1, the candidate will determine the primary physiologic mechanism(s) by which maternal genetic variants alter the risk of GDM. In Aim 2, the candidate will test whether the plasma of pregnant women contains endogenous beta-cell stimulatory activity which is deficient in GDM. To accomplish these aims, the candidate will study pregnant women in two cohorts: one established, with cross-sectional physiologic data and one actively enrolling, with longitudinal physiologic data. The proposed research may define key pathways leading to hyperglycemia in pregnancy which can be targeted in novel pregnancy- specific prevention and treatment strategies for GDM.